Project Summary: Cellular communication relies on the formation of specialized membrane structures and microdomains. Certain ion channels and receptors on the cell surface concentrate at these specific sites. Some of the signals responsible for this localization are secreted proteins that comprise the extracellular matrix (ECM). Originally thought to provide mostly structural support, the ECM has more recently been shown to play a role in organization of channels and receptors on neurons. Mechanosensory neurons represent a system where the influence of ECM proteins on receptor organization was recently identified. Sensation of mechanical stimuli is an important biological process that underlies senses of touch, proprioception, audition, and equilibrioception. The best-characterized eukaryotic mechanosensory system is sensation of gentle touch to the body in Caenorhabditis elegans. C. elegans gentle touch is transduced by the Na+permeable MEC-4 ion channel complex, which is localized in a punctate pattern along the processes of touch neurons. A specialized extracellular matrix, the mantle, surrounds the long sensory processes of touch neurons. Three ECM proteins, MEC-1, MEC-5, and MEC-9, are necessary for the proper localization of the MEC-4 channel and for touch sensitivity, but little is known about the molecular mechanisms responsible for these functions. One attractive hypothesis is that the ECM proteins form a direct tether to the MEC-4 channel complex. The broad research objectives of this project are to elucidate how ECM proteins localize surface receptors, and outcomes of this localization on receptor function. Studying ECM proteins of the C. elegans touch system will also enhance understanding of mechanosensory .mechanisms. Experiments will characterize localization and function of mantle and MEC-4 channel complex proteins during development. Additional investigations will assay for biochemical interactions between the ECM and channel proteins and ascertain the role of these interactions in touch sensation. PUBLIC HEALTH RELEVANCE: This study will enhance basic understandings of how molecules organize in the body during development. This information may benefit future studies of diseases particularly those of the brain. It will also help understand the workings of touch, hearing, and balance.